Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues
Paul J Peters1, Maria J Dueñas-Decamp, W Matthew Sullivan
1Center for AIDS Research, Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 373 Plantation Street Biotech II Suite 315, Worcester, MA 01605, USA.
Abstract:
Human immunodeficiency virus (HIV)-positive individuals frequently suffer from progressive encephelopathy, which is characterized by sensory neuropathy, sensory myelopathy, and dementia. Our group and others have reported the presence of highly macrophage-tropic R5 variants of HIV-1 in brain tissue of patients with neurological complications. These variants are able to exploit low amounts of CD4 and/or CCR5 for infection and potentially confer an expanded tropism for any cell types that express low CD4 and/or CCR5. In contrast to the brain-derived envelopes, we found that envelopes from lymph node tissue, blood, or semen were predominantly non-macrophage-tropic and required high amounts of CD4 for infection. Nevertheless, where tested, the non-macrophage-tropic envelopes conferred efficient replication in primary CD4(+) T-cell cultures. Determinants of R5 macrophage tropism appear to involve changes in the CD4 binding site, although further unknown determinants are also involved. The variation of R5 envelopes also affects their sensitivity to inhibition by ligands and entry inhibitors that target CD4 and CCR5. In summary, HIV-1 R5 viruses vary extensively in macrophage tropism. In the brain, highly macrophage-tropic variants may represent neurotropic or neurovirulent viruses. In addition, variation in R5 macrophage tropism may also have implications (1) for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and (2) for pathogenesis and depletion of CD4(+) T cells (i.e., do highly macrophage-tropic variants confer a broader tropism among CD4(+) T-cell populations late in disease and contribute to their depletion?).
Insights
Human immunodeficiency virus (HIV)-1 R5 variants show significant differences in macrophage tropism. Brain-derived HIV variants are highly macrophage-tropic, potentially contributing to neuroinflammation and disease progression.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Human immunodeficiency virus (HIV)-positive individuals often experience progressive encephalopathy, including neuropathy, myelopathy, and dementia.
- Macrophage-tropic R5 variants of HIV-1 have been identified in the brain tissue of patients with neurological complications.
Purpose of the Study:
- To investigate the tropism of HIV-1 R5 envelopes derived from different tissues (brain, lymph node, blood, semen).
- To understand the determinants of macrophage tropism and its implications for HIV pathogenesis and transmission.
Main Methods:
- Analysis of HIV-1 envelope proteins from various tissue sources.
- Infection assays using cells expressing different levels of CD4 and CCR5.
- Assessment of tropism variation and sensitivity to entry inhibitors.
Main Results:
- HIV-1 envelopes from brain tissue exhibited high macrophage tropism, utilizing low CD4/CCR5 levels.
- Envelopes from lymph nodes, blood, and semen were predominantly non-macrophage-tropic, requiring high CD4 levels.
- Determinants of macrophage tropism involve the CD4 binding site, with additional unknown factors.
Conclusions:
- HIV-1 R5 viruses display extensive variation in macrophage tropism.
- Highly macrophage-tropic variants in the brain may be neurotropic or neurovirulent.
- Tropism variation impacts HIV transmission, pathogenesis, and CD4+ T-cell depletion.
